Obsessive-Compulsive Disorder (OCD) is characterized by a lack of cognitive (effortful) control over repetitive thoughts (obsessions) and behaviors (compulsions) and is associated with dysfunction in fronto- striatal circuits. Treatment of OCD with serotonin reuptake inhibitors (SRIs) results in a long lag time (2-3 months) before clinical benefit that is typically only partially effective. Identification of effective, fast-actig treatments will help prevent OCD morbidity. We found that a single IV infusion of an N-methyl-D-Aspartate (NMDA) receptor antagonist, ketamine, can rapidly reduce OCD severity in the absence of an SRI. Animal studies find fronto-striatal activity modulation is a critical driver of OCD-like repetitive behaviors, with knockout of a gene encoding a postsynaptic scaffolding protein at glutamate synapses leading to altered fronto-striatal activity, OCD-like behavior, and elevated expression of NMDAR subunits. Taken together, these studies support the NMDA receptor as a promising new target for OCD-relevant behaviors. This R01 will test the acute mechanism of ketamine's therapeutic action in adults with OCD at the level of molecules, circuits, and network synchrony. We use a novel approach to simultaneously study both spatial and temporal functional brain changes caused by NMDA receptor antagonism. Current theories posit that the fronto-striatal hyperactivity observed in OCD at baseline is due to dysfunction in inhibitory and excitatory neural networks. Consistent with these theories, we find deficits in the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in the medial prefrontal cortex (MPFC) in OCD compared to healthy controls. We also discovered that OCD subjects given a single dose of IV ketamine show a significant increase of MPFC GABA 1 hour post-infusion. In healthy controls, increases in prefrontal GABA are correlated with the induction of gamma oscillations, a potential biomarker for local inhibitory circuits within this region. Based on our findings, we propose a testable working model for how the ketamine may decrease OCD severity that links GABA, functional connectivity in frontal- striatal circuits, and network synchrony. The overall goal of this R01 is to determine how NMDA receptor antagonism modifies disease-specific pathology to relieve repetitive thoughts and behaviors. The proposed projects use a multimodal imaging approach across multiple units of analysis (molecules, circuits, and network synchrony) in order to open a new avenue for rapid acting therapeutics (with NMDAR antagonism as a first new target) to transform psychiatric treatments.